The mammalian atrium produces a group of peptides known collectively as the atrial natriuretic factor (ANF). The peptides now have been shown to possess potent diuretic, antihypertensive and smooth muscle relaxant properties. Prior to 1981, the existence of this active principle had been only the subject of a proposition. However, in the early part of this decade two pioneering experiments demonstrated the existance and important properties of this factor; namely, A. J. de Bold et al., Life Sciences, 28, 89 (1981) reported that an injection of an extract of rat cardiac atria produced an immediate and potent diuretic response in the rat. Two years later, M. G. Currie et al, Science, 221, 71 (1983) reported that a rat cardiac atria extract possessed potent smooth muscle relaxant activity. Since these reports, a great deal of attention has been directed to the structure elucidation of the substances that comprise ANF, and to investigations of the role ANF in nature's regulation of body fluid volume and blood pressure. For a review of these developments, see M. Cantin and J. Genest, Endocrine Reviews, 6, 107 (1985). Briefly, with reference to the elucidation of the ANF substances, the active principle in the rat atrium has been shown to be derived from a prohormone containing 152 amino acids. In human atrium, a corresponding prohormone containing 151 amino acids has been identified. Subsequent investigations have established that fragments of the prohormones containing from about 20 to 33 amino acids are more potent that the prohormones themselves, provided that the fragments still contain the C-terminus portion and the cyclic structure of the prohormone. The cyclic structure results from an intramolecular disulfide bridge formed between two half cystine residues at positions 105 and 121 of the peptide sequence. An example of such a fragment of the rat prohormone is rat ANF-(101-126) which has the following structure: ##STR1##
The corresponding fragment of the human prohormone, human ANF-(101-126), has the same structure except for the replacement of the isoleucyl residue at 110 by a methionyl residue.
Chemists now have synthesized the smaller, more active peptides (i.e. fragments) thus making them readily available for extensive biological investigations and for possible development as diuretic and antihypertensive agents. However, the development of the natural peptides is hampered by their rapid decomposition in vivo by enzymatic processes. Accordingly several investigators are now looking at derivatives or analogs of the natural atrial peptides as a source for potential drugs with improved stability, potency and/or duration of action over the natural peptides. For example, see J. Rivier and F. Edouard, PCT patent application W085/04872, published Nov. 7, 1985; Japanese patent application No. 61243100, published Oct. 29, 1987, and S. Sakakibara, U.S. Pat. No. 4,670,540, issued June 2, 1987. The present application discloses new atrial peptide derivatives having a favorable biological profile which renders them useful as antihypertensive agents and for the treatment of pathological conditions resulting from an imbalance of body fluids and/or electrolytes.